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Human Molecular Genetics, 2003, Vol. 12, No. 7 777-789
DOI: 10.1093/hmg/ddg087
© 2003 Oxford University Press

Non-syndromic vestibular disorder with otoconial agenesis in tilted/mergulhador mice caused by mutations in otopetrin 1

Belen Hurle1, Elena Ignatova2, Silvia M. Massironi3, Tomoji Mashimo4, Xavier Rios1, Isolde Thalmann2, Ruediger Thalmann2 and David M. Ornitz1,*

1Department of Molecular Biology and Pharmacology, and 2Department of Otolaryngology, Washington University Medical School, 660 South Euclid Ave, St Louis, MO 63110, USA, 3Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, Av. Professor Lineu Prestes, 1730, Cidade Universitária, CEP 05508-900, São Paulo, SP, Brazil and 4Unite de Genetique des Mammiferes, Institut Pasteur, 25 Rue du Docteur Roux, F-75724 Paris Cedex 15, France

Received December 10, 2002; Accepted February 5, 2003

Otoconia are biominerals within the utricle and saccule of the inner ear that are critical for the perception of gravity and linear acceleration. The classical mouse mutant tilted (tlt) and a new allele, mergulhador (mlh), are recessive mutations that affect balance by impairing otoconial morphogenesis without causing collateral deafness. The mechanisms governing otoconial biosynthesis are not known. Here we show that tlt and mlh are mutant alleles of a novel gene (Otopetrin 1, Otop1), encoding a multi-transmembrane domain protein that is expressed in the macula of the developing otocyst. Both mutants carry single point mutations leading to non-conservative amino acid substitutions that affect two putative transmembrane (TM) domains (tlt, Ala151->Glu in TM3; mlh, Leu408->Gln in TM8). Otop1 and Otop1-like paralogues, Otop2 and Otop3, define a new gene family with homology to the C. elegans and D. melanoganster DUF270 genes.

* To whom correspondence should be addressed. Email: dornitz{at}molecool.wustl.edu


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